PROJECT SUMMARY Antibiotic resistance is one of the greatest threats to human health. It is quickly becoming evident that current research efforts are unable to keep pace with the rate at which bacteria evolve inactivation mechanisms to last- resort antibiotics. The core structures of many of these last-resort compounds are small, flat, structurally sparse heterocycles amenable to rapid diversification by chemical semi-synthesis. However, recent major campaigns aimed at improving resistance have yielded only a small number of FDA-approved antibacterials derived from these molecules. Structurally-rich antibiotics, like vancomycin and pleuromutilin, have comparatively vast chemical and structural space that remains essentially unexplored. In particular, nearly 1200 derivatives of pleuromutilin have been synthesized since its discovery in 1951, but due to the sheer structural complexity of pleuromutilin, the majority of derivatives are semi-synthetic congeners of the glycolic acid side-chain. Much effort has been devoted to a total chemical synthesis of pleuromutilin, but only one such synthesis exists. The 34 linear steps required to prepare pleuromutuilin is both infeasible for large-scale production and does not allow for the rapid synthesis of congeners designed to probe fundamental questions regarding the metabolic degradation and biological activity of this important antibiotic. We propose the first highly convergent total chemical synthesis of pleuromutilin, in which two rapidly prepared building blocks are united by a regio- and stereospecific nickel-catalyzed reductive coupling at a late stage in the synthesis. A second key step leverages our expertise in organosamarium-mediated reductive cyclizations to forge a hindered carbon-carbon bond and establish three stereocenters. Taken together, these strategies will enable expedient access to pleuromutilin, allow for a much broader diversity of studies on the core carbon skeleton, facilitate derivatization efforts aimed at the much-needed development of new antibiotics, and contribute knowledge to the chemistry and biology of pleuromutilin.